A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus
A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus
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DOI：
10.1073/pnas.1904700116
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发表时间：
2019-08-13
影响因子：
11.1
通讯作者：
Mylonakis, Eleftherios
中科院分区：
文献类型：
--
作者：
Kim, Wooseong;Zou, Guijin;Mylonakis, Eleftherios
金黄色葡萄球菌感染的治疗由于抗生素耐受性的发展而变得复杂，这是金黄色葡萄球菌能够在体内产生耐药性的结果。金黄色葡萄球菌进入非生长的休眠状态，其中生物体被称为持留菌。我们报告，临床批准的驱虫剂bithionol杀死耐甲氧西林沙门氏菌。金黄色葡萄球菌（MRSA）的持久性细胞，这与其破坏革兰氏阳性细菌膜的完整性的能力相关。关键的是，与哺乳动物细胞膜相比，双硫堇对细菌具有显著的选择性。全原子分子动力学（MD）模拟表明，bithionol的细菌膜的选择性与其渗透和嵌入在细菌模拟脂质双层的能力，但不是在富含胆固醇的胆固醇模拟脂质双层。除了引起快速的膜透化，连硫二酚的插入增加膜流动性。通过使用bithionol和nTZDpa（另一种膜活性抗菌剂），以及这些化合物的类似物，我们表明，膜活性化合物对MRSA持久性的活性与其增加膜流动性的能力呈正相关，从而建立了一个准确的生物物理指标，用于估计抗persister效力。最后，我们证明，在与庆大霉素，bithionol有效地减少细菌负荷的慢性深部MRSA感染的小鼠模型。这项工作突出了bithionol作为抗persister治疗剂的潜在再利用。
Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.